rs4631890

Variant names:

• chr11-121487652-G-A
• rs4631890
• NM_003105.6:c.529-380G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003105.6(SORL1):​c.529-380G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 152,010 control chromosomes in the GnomAD database, including 17,358 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17358 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 10 publications found

Genes affected

SORL1 (HGNC:11185): (sortilin related receptor 1) This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]

SORL1 Gene-Disease associations (from GenCC):

• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.529-380G>A		intron_variant	Intron 3 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.529-380G>A		intron_variant	Intron 3 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.481-380G>A		intron_variant	Intron 3 of 14	1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72120 AN: 151892 Hom.: 17350 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.466

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.475 AC: 72164 AN: 152010 Hom.: 17358 Cov.: 32 AF XY: 0.476 AC XY: 35398 AN XY: 74294

African (AFR) AF: 0.477 AC: 19771 AN: 41458

American (AMR) AF: 0.507 AC: 7752 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2069 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1614 AN: 5170

South Asian (SAS) AF: 0.394 AC: 1899 AN: 4814

European-Finnish (FIN) AF: 0.461 AC: 4868 AN: 10558

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.478 AC: 32471 AN: 67944

Other (OTH) AF: 0.461 AC: 972 AN: 2108

Alfa AF: 0.483 Hom.: 30625

Bravo AF: 0.477

Asia WGS AF: 0.344 AC: 1196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.59
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4631890; hg19: chr11-121358361;